Electrogenerated base-promoted cyclopropanation using alkyl 2-chloroacetates

The electrochemical reduction conditions of the reaction of alkyl 2-chloroacetates in Bu4NBr/DMF using a divided cell equipped with Pt electrodes to produce the corresponding cyclopropane derivatives in moderate yields were discovered. The reaction conditions were optimized, the scope and limitations, as well as scale-up reactions were investigated. The presented method for the electrochemical production of cyclopropane derivatives is an environmentally friendly and easy to perform synthetic procedure.


S1
1. General remarks 1 H NMR and 13 C NMR spectra were carried out by using a Varian MERCURY 300 ( 1 H NMR 300 MHz, 13 C NMR 75 MHz) and a JEOL JNM-ECS 400 ( 1 H NMR 400 MHz, 13 C NMR 100 MHz) spectrometer. Unless otherwise noted, CDCl3 was used as the solvent. In 1 H NMR, residual solvent (CHCl3, 7.26 ppm) or tetramethylsilane (0.00 ppm) was used as internal standard. In 13 C NMR of CDCl3, the chemical shift is referenced to the signal at 77.0 ppm. High-resolution mass spectra (HRMS) were measured using a Thermo Fisher Scientific Exactive Plus spectrometer. Merck precoated silica gel F254 plates (thickness 0.25 mm) were used for the TLC analysis. A silica gel column (Kanto Chem. Co., Silica Gel N, spherical, neutral, 40-100 μm) was used for the flash chromatography using an air pump. An LC-9201, LC-9110 NEXT, or LC-9210 NEXT apparatus, equipped with JAIGEL-1H and JAIGEL-2H, was used for the preparative GPC separation with recycle mode, and CHCl3 was used as an eluent. Gas chromatography was performed by using a Shimadzu GC-2014 apparatus, equipped with a capillary column and FID. Electrochemical reactions were carried out using a power supply such as a KIKUSUI PMC350-0.2A and PMX350-0.2A. All reactions were conducted under an N2 atmosphere.

Synthesis of n-propyl 2-chloroacetate (9)
A three-necked round flask was dried by heating gun under reduced pressure, and filled afterwards with N2.
To the flask, chloroacetic acid (9.45 g, 100 mmol), n-propanol (100 mL), and 98% sulfuric acid (2.0 mL) were added. The solution was refluxed for 24 h. After the reaction, the solution was evaporated under reduced pressure to remove the solvent. Then, the residue was poured into H2O (250 mL), and S2 the mixture was neutralized by the addition of aq. 10% NaHCO3. The mixture was extracted with Et2O (20 mL × 3), and the combined organic phase was washed with H2O (30 mL × 2). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by distillation under atmospheric pressure to give n-propyl 2-chloroacetate (9, 2.80 g, 20.5 mmol, 21% yield), which was identified by comparison of the reported spectroscopic data [1].

General procedure for the formation of cyclopropane derivatives (Table 1, entry 1).
Cathodic reduction was carried out in an H-type divided cell (4G glass filter) equipped with two platinum plates in anode and cathode (1 cm × 2 cm). After drying and replacement by N2, 0.3 M Bu4NBr/DMF (4.0 mL × 2) was added to anode and cathode. In the cathodic chamber, 1 (75.6 mg, 0.502 mmol) was added and stirred. The reduction was carried out by using 12 mA until 1.0 F/mol was consumed. After the electrolysis, the solutions of the cathode and anode were collected and poured into 10% Na2S2O3 (20 mL) and hexane/AcOEt (4:1) (10 mL). Additional hexane/AcOEt (4:1) (10 mL) was used to collect the organic materials from the H-type divided cell. To the mixture, hexane/AcOEt (4:1) (20 mL) was added and separated. The aqueous phase was extracted with hexane/AcOEt (4:1) (20 mL × 2). The combined organic phase was washed by brine (10 mL), dried over Na2SO4, filtered and concentrated. A short column was also carried out with hexane/AcOEt (3:1).

Gram-scale synthesis of 2 from 1 (Table 4, entry 1).
Cathodic reduction was carried out in an H-type divided cell (4G glass filter) equipped with two platinum plates as anode and cathode (2 cm × 2 cm). After drying and replacement with N2, 0.3 M Bu4NBr/DMF (30 mL × 2) was added to anode and cathode. In the cathodic chamber, 1 (1.205 g, 8.0 mmol) was added and stirred. The reduction was carried out by using 12 mA until 1.0 F/mol was consumed. After the electrolysis, the solutions of the cathode and the anode were collected and poured into 10% Na2S2O3 (150 mL) and hexane/AcOEt (4:1) (20 mL). Additional hexane/AcOEt (4:1) (20 mL) was used to collect the organic materials from the H-type divided cell. To the mixture, S4 hexane/AcOEt (4:1) (50 mL) was added and separated. The aqueous phase was extracted with hexane/AcOEt (4:1) (50 mL × 2). The combined organic phase was washed with brine (30 mL), and dried over Na2SO4, filtered and concentrated. A short column was also carried out with hexane/AcOEt (3:1). The solution was concentrated to give the crude material, which was purified by using preparative GPC separation with recycle mode to give 2 (409.8 mg, 1.20 mmol, 45% yield), in which the connected JAIGEL-1H-40 and JAIGEL-2H-40 were used.